Structure of a nanobody-stabilized active state of the β2 adrenoceptor

By S. Rasmussen, Hee-Jung Choi, J. Fung, E. Pardon, P. Casarosa, P. S. Chae, Brian T DeVree, D. Rosenbaum, Foon Sun Thian, T. S. Kobilka and 8 more. Nature, 2011

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G protein coupled receptors (GPCRs) exhibit a spectrum of functional behaviours in response to natural and synthetic ligands. Recent crystal structures provide insights into inactive states of several GPCRs. Efforts to obtain an agonist-bound active-state GPCR structure have proven difficult due to the inherent instability of this state in the absence of a G protein. We generated a camelid antibody fragment (nanobody) to the human β2 adrenergic receptor (β2AR) that exhibits G protein-like behaviour, and obtained an agonist-bound, active-state crystal structure of the receptor-nanobody complex. Comparison with the inactive β2AR structure reveals subtle changes in the binding pocket; however, these small changes are associated with an 11 Å outward movement of the cytoplasmic end of transmembrane segment 6, and rearrangements of transmembrane segments 5 and 7 that are remarkably similar to those observed in opsin, an active form of rhodopsin. This structure provides insights into the process of agonist binding and activation.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/8837ea586b2ed4df317249ac051cd5677cda7975

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Citations in the corpus

Structural insights into the dynamic process of β2-adrenergic receptor signaling (2015, positive): “Nb80 was purified as previously described (Rasmussen et al., 2011a).”
International Union of Basic and Clinical Pharmacology. LXXXIX. Update on the Extended Family of Chemokine Receptors and Introducing a New Nomenclature for Atypical Chemokine Receptors (2014, neutral): “This motif, and in particular the positive charge (position III:261, or 3.50), is important for 7TM receptor activation, as emphasized by direct interaction with G protein in the recent crystal structure of an active 7TM receptor, the b2-adrenergic receptor, in complex with the Gas-subunit (Rasmusse”